1. Field of the Invention
The present invention relates in general to a new, simple, and easy process for preparing cephalosporin antibiotics including ceftazidime, cefixime, and the like. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the following formula (I), in which a 7-amino cephalosporanic acid derivative of the following formula (III) is acylated by reaction with a new crystalline aminothiazole derivative of the following formula (II) in a solvent: 
wherein R1 and R2 are the same or different and independently represent H, an alkyl group of 1 to 4 carbon atoms, or a cycloalkyl group of 3 to 5 carbon atoms, etc., R4 represents acetoxymethyl, pyridiniummethyl, or vinyl, COOM is COOxe2x88x92 when R4 is pyridiniummethyl and COOH otherwise, and X represents chlorine or bromine. Moreover, the acid in the acid addition salt as shown in the formula (II) represents an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, or perchloric acid, etc., or an organic acid, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, or benzenesulfonic acid, etc.
2. Description of the Prior Art
Processes for the preparation of cephalosporin antibiotics of the above formula (I), including ceftazidime and cefixime, were disclosed in several literatures and patents, for example, U.S. Pat. No. 4,258,041; Austrian Patent Publication Nos. 86-2427 and 86-2428; J. of Antibiotics, Vol.38, pp. 1738, 1985; and Korean Patent Publication Nos. 84-1827, 84-1987, 84-1988, 84-1989, 84-1990, 87-1807, and 93-7810.
In the above prior processes, an amino group of a 3-cephem compound represented by the following formula (I-1) is acylated by reaction with a 2-aminothiazol carboxylic acid of the following formula (I-2) or a salt or reactive derivative thereof to produce the cephalosporin derivative of the formula 
where R1, R2, and R4 have the same meanings as described above, R3 is a carboxy protecting group, Ra is hydrogen or an amino protecting group, Rb is hydrogen or a carboxy protecting group, such as diphenylmethyl or p-nitrobenzene.
U.S. Pat. No. 4,258,041, and Korean Patent Publication No. 84-1827, etc. describe processes employing acid chloride of the organic acid (I-2) in the acylation reaction with the 7-amino cephalosporin derivative of the formula (I-1). According to these processes, the organic acid (I-2) is conventionally protected on an amino group of its thiazole ring, and then converted to its acid chloride with thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride, etc. Thereafter, the resulting acid chloride of the organic acid (I-2) is reacted with the 7-amino cephalosporanic acid derivative, followed by removing the protecting group on the amino group of the thiazole ring. However, these processes have disadvantages in that they are carried out under strict reaction conditions, and further require a step of protecting the amino group of the thiazole ring and a step of removing the protecting group on the amino group. In addition, another drawback with these processes is that the aminothiazole compound activated with unstable acid chloride is acylated as such without being subjected to an isolation step, such that by-products are significantly produced during the acylation reaction owing to the unstable acid chloride.
Austrian Patent Publication Nos. 86-2427 and 86-2428, and WO No. 98-31685, etc. disclose processes in which a reactive ester of the organic acid (I-2) is prepared and acylated. In this acylation, the reactive ester of the organic acid (I-2) may be reacted with the 7-aminocephalosporin derivative without the protecting group on the amino group of its thiazole ring. However, it is necessary for these processes to remove a protecting group on a carboxy group of the aminothiazole compound (I-2) after the acylation reaction, in order to give the final desired compound.
In addition, there are also known other processes employing a reactive amide or a mixed acid anhydride, but they have drawbacks similar to those in the above processes.
Therefore, in the case of carrying out the acylation reaction using the reactive derivative (e.g., the acid chloride) as described above, the amino and carboxyl groups of the compound of the formula (I-2) must be protected with Ra other hand, in the case of using the reactive ester, the preparation of the reactive ester must be carried out in a state where the amino group is not protected, but the carboxyl group is protected with R3. As a result, all the processes according to the prior art have a drawback in that the deprotection must be carried out after the acylation reaction.
We have discovered that, when an aminothiazole compound represented by the following formula II was acylated by reaction with a 7-amino cephalosporanic acid derivative represented by the following formula (III) in a solvent as indicated in the following reaction scheme, a desired compound could be directly obtained in a high yield in a simple and easy way without a need of the deprotection after the acylation reaction, whereby we have perfected the present invention based on this discovery: 
wherein R1, R2, R4, and the acid addition salt have the same meaning as defined above.
It is therefore an object of the present invention to provide a process for preparing cephalosporin antibiotics including ceftazidime and cefixime, etc., using a new aminothiazole compound represented by the formula (II).
The foregoing and other objects, features and advantages of the invention will be apparent to those skilled in the art to which the present invention relates from reading the following specification.
The aminothiazole compound of the formula (II) used as the starting material in the practice of the present invention is a new material and a reactive derivative in the form of a crystalline acid chloride. Thus, this is more stable and can be stored over a lengthy period of time at a low temperature and room temperature, as compared with the conventional acid chloride. Moreover, the process of the present invention produces little or no by-products in the acylation reaction of the 7-aminocephalosporin derivative with the compound of the formula (II), and is also relatively short in reaction time. Additionally, the process of the present invention employing this compound of the formula (II) does not require the removal of the protecting group after the acylation, and allows the desired compound to be directly obtained after the acylation. As a result, the process of the present invention makes the acylation reaction more economical and also simple and easy.
The new aminothiazole derivative of the formula (II) is described in detail in Korean Patent Application No.2000-11127 (Filing date: Mar. 6 2000; Name of Applicant: HANMI FINE CHEMICALS, CO., LTD; and Title: New thiazole compounds and a process thereof), the disclosure of which is incorporated herein by reference. Moreover, among the derivatives of the formula (III), a 3-vinyl-7-aminocephalosporanic acid and a 3-pyridiniummethyl-7-aminocephalosporanic acid mentioned herein are known compounds and described in detail in several literatures, for example, U.S. Pat. No. 4,423,213, Korean Patent No. 127,113, and British Patent No. 2,052,490, the disclosure of which is incorporated herein by reference.
In the acylation reaction according to the present invention, the compound of the formula (II) is used in the amount of 1.0 to 2.0 equivalents, and preferably 1.2 to 1.4 equivalents, relative to the compound of the formula (III).
The solvent which can be used in the practice of the present invention includes, for example, dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, methanol, ethanol, or a combination thereof. However, a solution adjuvant, such as N,O-bistrimethylsilylacetamide, trimethylchlorosilane, or trimethyliodosilane, etc., may also be used in combination with the solvent in the present invention depending on the kind of the 7-cephalosporin derivative.
The solvent is used in the amount of 5 ml to 30 ml, and preferably 10 ml to 15 ml, relative to 1 g of the compound of the formula (II). The acylation reaction according to the present invention is preferably carried out at a temperature of xe2x88x9210xc2x0 C. to 30xc2x0 C.
The acylation reaction of the present invention is generally carried out without the use of a base, although an organic or inorganic base may also be used depending on the 7-aminocephalosporin derivative. If used, the base is used in the amount of 1.0 to 3.0 equivalents. Examples of the organic base which can be used in the present invention include tri-(n-butyl)amine, diisopropylethylamine, pyridine, dicyclohexylamine, and the like. Moreover, the acylation reaction may also be carried out in a mixed solution of a basic aqueous solution and the organic solvent, with the basic aqueous solution being preferably an aqueous solution of sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, or sodium hydroxide, etc.
In this acylation reaction, water and the organic solvent are preferably used in the volume of 10 times to 20 times relative to the compound of the formula (II), with the volume ratio of water to the organic solvent being 1/4 to 1/10.
As described above, the process for the preparation of the cephalosporin derivative is characterized in that the compound of the formula (III) is reacted with the new thiazole compound of the formula (II), as the reactive organic acid derivative, to give the cephalosporin derivative of the formula (I). Such a process does not require the deprotection step and is reduced in production step, as compared with the processes according to the prior art. Furthermore, as the reactive acid derivative used in the process of the present invention is the acid chloride of the stable crystalline form, the acylation reaction with the compound of the formula (II) can be completed clean in a quantitative view with little or no production of by-products. In addition, the compound of the formula (II) can be stored in the form of acid chloride and is thus easy to use. As a result, the present invention provides the more inexpensive and new acylation process for the preparation of the cephalosporin derivatives having the compound of the formula (II) at a 7-position.